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PubMed1987

Release of gamma-aminobutyric acid and acetylcholine by neurotensin in guinea-pig ileum.

The release of gamma-aminobutyric acid (GABA) and acetylcholine (ACh) from the strips of guinea-pig ileum was investigated in the presence of neurotensin. Neurotensin evoked the release of [3H]-GABA from the strips preloaded with [3H]-GABA, and the evoked release was Ca2+-dependent and tetrodotoxin-sensitive. Hexamethonium, scopolamine, [D-Pro2,D-Trp7,9] substance P and pretreatment with substance P did not alter the neurotensin-evoked release of [3H]-GABA. Pretreatment with neurotensin inhibited the release of [3H]-GABA evoked by neurotensin but not by high K+, thereby indicating that neurotensin induced a specific desensitization of its own receptor. These observations indicate that neurotensin may stimulate the GABAergic neurone through its own receptor. Neurotensin evoked the release of [3H]-ACh from strips preloaded with [3H]-choline and this release was Ca2+-dependent and tetrodotoxin-sensitive. The evoked release of [3H]-ACh was not affected by hexamethonium, scopolamine and [D-Pro2,D-Trp7,9] substance P. Bicuculline partly inhibited the neurotensin-evoked release of [3H]-ACh; thus neurotensin seems to induce a release of ACh partly through the release of endogenous GABA. All this evidence indicates that neurotensin induces release of GABA as well as ACh from the myenteric neurones of the guinea-pig ileum.

Acetylcholine↗
PubMed1983

Effects of gamma-aminobutyric acid on neural regulation of the canine sinus node.

The direct effects of gamma-aminobutyric acid (GABA) on the sinus node and its neural regulation were studied by selective perfusion of the sinus node artery (SNA) in 26 open-chest pentobarbital-anesthetized dogs. GABA (1-1,000 micrograms/ml, 2 ml, SNA) produced no direct effect on intrinsic sinus rate, but in several experiments (at 1 microgram/ml) it produced an inconsistent augmentation of the sinus tachycardia due to right stellate stimulation. At all other concentrations tested (10-1,000 micrograms/ml), GABA did not significantly alter the sinus node response to stellate stimulation. Local alpha-receptor blockade with phentolamine or muscarinic receptor blockade with atropine through the SNA prior to the perfusion of GABA did not change the sinus node responses. GABA (10-1,000 micrograms/ml, 2 ml, SNA) significantly attenuated (by 45-80% of control) the sinus bradycardia due to stimulation of the right vagosympathetic trunk. The sinus node response to selective perfusion of norepinephrine or acetylcholine (0.01 micrograms/ml, 2 ml, SNA) was not affected by GABA. The stellate augmentation (when present) and vagal attenuation were both antagonized by perfusion of picrotoxin (1,000 micrograms/ml, 2 ml, SNA). It is concluded that GABA does not exert any direct effect on the sinus node but may indirectly influence sinus rate by an effect on local nerves or ganglia.

Animals↗
PubMed1990

Presynaptic effects of gamma-aminobutyric acid on norepinephrine release and uptake in rat pineal gland.

The effect of tau-aminobutyric acid (GABA) on pineal norepinephrine (NE) release was examined in vitro in the rat pineal gland. Exposure of pineal explants previously loaded with 3H-NE to 1-100 microM GABA caused a dose-dependent decrease of 3H-NE release triggered by 60 mM K+, with a threshold GABA concentration of 1 microM and IC50 of about 10 microM. The inhibitory effect of GABA was mimicked by the type B GABA agonist baclofen, displaying a similar dose-response relationship as GABA. The type A GABA agonist muscimol increased depolarization-induced 3H-NE release, while the co-incubation with GABA and the type A receptor antagonist bicuculline augmented significantly GABA's depressive effect on 3H-NE release. Bicuculline alone brought about a significant decrease of 3H-NE release. Neither GABA, nor baclofen, muscimol or bicuculline, modified the spontaneous pineal 3H-NE efflux. Assessment of 3H-NE uptake at a low NE concentration (0.5 microM) indicated that GABA decreased it in a dose-dependent manner (IC50 = 100 microM) through an effect blocked by bicuculline and mimicked by muscimol but not by baclofen; at a 5 microM-3H-NE concentration a bicuculline-sensitive GABA augmentation of uptake was found. A kinetic analysis study of the pineal NE uptake process indicated that GABA augmented both Vmax and Km of transmitter uptake. These results indicate that GABA may be a significant regulatory signal for rat pineal sympathetic synapses.

Animals↗
PubMed1995

Glucose modulates gamma-aminobutyric acid release from the pancreatic beta TC6 cell line.

To determine if endogenous gamma-aminobutyric acid (GABA) is secreted by a pancreatic beta-cell-derived cell line and to determine the effects of glucose on GABA release, beta TC6 cultures were incubated in the presence of 1 or 10 mmol/l glucose for 12 h and then subjected to a 2-h secretion test in Krebs-Ringer buffer containing 1 or 10 mmol/l glucose. beta TC6-conditioned medium was collected at 15, 30, 60, and 120 min after glucose stimulation for GABA analysis by high pressure liquid chromatography-electrochemical detection. After 30 min, medium GABA concentrations were significantly higher (p < 0.05) in cultures that were exposed to high glucose during both the 12-h incubation period and the 2-h secretion test than in the remaining three glucose combinations. To address possible roles of beta-cell-derived GABA, the effect of GABA on glucagon secretion from pancreatic alpha TC6 cells was tested at concentrations released from beta TC6 cells. Inhibition of glucagon secretion by alpha TC6 cells was observed in the presence of GABA at concentrations equivalent to concentrations secreted by beta TC6 cells. The inhibitory effects of GABA on glucagon secretion by alpha TC6 cells were blocked by the GABAA receptor antagonist bicuculline and were dissociated from the inhibitory effects of glucose. Together, these results provide the first documentation that endogenous GABA is released from a highly differentiated beta-cell line and that glucose and GABA independently attenuate glucagon secretion by a pancreatic alpha-cell line.

Animals↗
PubMed2004

Co-expression of calretinin and gamma-aminobutyric acid in neurons of the entorhinal cortex of the common marmoset monkey.

The gamma-aminobutyric acid (GABA)-containing interneuron population in the entorhinal cortex has been shown to consist of several subpopulations. In addition to GABA, these neurons contain another neurochemical substance, such as a neuropeptide or a calcium binding protein. In the present study, we examined the co-localization of calretinin and GABA in the entorhinal cortex of the common marmoset Callithrix jacchus, a New World monkey. Although the function of calretinin remains unclear, there are indications that it might have a protective role against cell death in a number of neuropathological diseases. Furthermore, it might have a regulatory role in the neurotransmission of GABAergic neurons. In contrast to the rat brain, sparse data exist regarding the degree of co-expression of these two markers in the monkey brain. Using immunofluorescence and confocal laser scanning microscopy, we found that an average of 56% of the calretinin-positive neurons in the monkey entorhinal cortex contained GABA, whereas about 27% of the GABA-positive neurons co-expressed calretinin. Interestingly, these numbers were higher in the superficial layers of the entorhinal cortex in comparison with the deep layers. However, no differences were found in co-localization percentages between the different entorhinal subfields. In general, the degree of co-localization was higher in comparison to findings in the rat entorhinal cortex. The higher amount of co-localization observed in the present study might reflect species differences between the primate and the non-primate brain.

Animals↗
PubMed1986

Presence of gamma-aminobutyric acid in embryonic palates of AJ and SWV mouse strains.

The presence of gamma-aminobutyric acid (GABA) in the embryonic palate was sought as a criterion for its role in regulating palate development. GABA was measured by a gas chromatographic-mass spectrometric (GC-MS) method using the heptafluorobutyryl (HFB)-cyclohexyl-GABA derivative, which gave the necessary sensitivity and specificity to measure low levels of GABA in the presence of contaminating substances. GABA was measured in dissected embryonic palates at various times of development in the AJ mouse strain. GABA levels were lower in day 14 AJ palates (0.19 +/- 0.01 nmol/mg protein) than at days 13 (0.28 +/- 0.03) and 15 (0.30 +/- 0.04). Comparable levels were observed in fore- and hindlimbs at day 14, whereas levels were lower in embryonic tongue and higher, as was expected, in embryonic brain. To confirm the presence of GABA in the palate, it was analyzed in growing palate mesenchymal cells in primary and secondary cultures as well as in serum-free medium. In addition, GABA levels were compared in the SWV mouse strain; this strain exhibits a more efficient active uptake mechanism and diazepam produces a higher frequency of cleft palate in this strain than in AJ. SWV contained one and one-half to three times higher concentrations of GABA in excised palates and cultured palate cells than the AJ strain. Furthermore, when GABA levels in skin fibroblasts of the two strains were measured, SWV cells contained 2.7-fold greater GABA than AJ cells. The present results provide additional evidence for the role of GABA in palate development.

Amniotic Fluid↗
PubMed1987

Gamma-aminobutyric acid and dysregulation of TSH secretion in uremic male rats.

The role of gamma-aminobutyric acid (GABA) in the abnormal secretion of thyrotropic hormone (TSH) in uremia was studied in male Sprague-Dawley rats rendered renally insufficient by subtotal nephrectomy. Baseline TSH concentrations in normal control animals and in the uremic animals were similar. The peak TSH response to thyrotropin-releasing hormone (TRH; 5 micrograms i.v.) was significantly blunted in the uremic animals compared to the controls. Pretreatment of the uremic animals with the specific GABA antagonist, bicuculline (1.5 mumol i.v.) resulted in normalization of the peak TSH response to TRH. Bicuculline pretreatment, however, did not alter the basal secretion of TSH in either the normal or the uremic animals, and it also did not augment the TRH-stimulated TSH response in the normal animals. Sham-operated animals demonstrated basal and TRH-stimulated TSH responses comparable to the control group. In order to assess whether the weight loss associated with uremia could have accounted for the blunted TRH-stimulated TSH secretion in the uremic animals, a group of rats were starved so that their weights were comparable to those of the uremic animals. Basal and TRH-stimulated TSH responses in this group were not significantly different from the controls. Bicuculline pretreatment of the starved animals also failed to alter the basal and TRH-stimulated TSH responses. These data indicate that an increase in central gabaergic tone may be partly responsible for the blunted TSH response to TRH seen in uremia, but that GABA is not an important modulator of TSH secretion in the normal rat.

Animals↗
PubMed1985

Possible involvement of K+-conductance in the action of gamma-aminobutyric acid in the guinea-pig hippocampus.

The mechanism underlying the action of gamma-aminobutyric acid (GABA) in the hippocampus was investigated using guinea-pig brain slices. GABA either superfused or applied directly by microiontophoresis produced a biphasic response in pyramidal cells, comprising hyperpolarizing and depolarizing components. When different concentrations of GABA were applied to the same neurone, the lower concentrations generally produced a hyperpolarization-predominant response, while higher concentrations resulted in a depolarization-predominant response. The depolarizing component of the response to GABA was augmented in a medium containing a low concentration of Cl-, relatively unaffected by a change in external K+ concentration, and blocked by picrotoxin (2 X 10(-5) M). The depolarizing response to GABA persisted in a Ca2+-free medium in which the concentration of Na+ was reduced to 13 mM. Combined application of low doses of picrotoxin and bicuculline eliminated the major part of the depolarizing component of the biphasic response to GABA and produced a relatively pure hyperpolarizing response. The reversal potential of this pharmacologically 'isolated' hyperpolarizing response to GABA was estimated, from the current-voltage relationships, to be about -90 mV and was the same as that of the hyperpolarization induced by baclofen. When the membrane was successively hyperpolarized by inward direct current (d.c.) injections, the reversal point of the 'pharmacologically isolated' hyperpolarizing response to GABA coincided with that of the post-burst hyperpolarization. Low concentrations of Cl- in the bathing medium had no noticeable effect on the hyperpolarizing component of the response to GABA, whereas it markedly increased the amplitude of the depolarizing component. These results suggest that the action of GABA in the hippocampus may involve an activation of K+ conductance.

Animals↗
PubMed2004

Differential protein mobility of the gamma-aminobutyric acid, type A, receptor alpha and beta subunit channel-lining segments.

The gamma-aminobutyric acid, type A (GABAA), receptor ion channel is lined by the second membrane-spanning (M2) segments from each of five homologous subunits that assemble to form the receptor. Gating presumably involves movement of the M2 segments. We assayed protein mobility near the M2 segment extracellular ends by measuring the ability of engineered cysteines to form disulfide bonds and high affinity Zn(2+)-binding sites. Disulfide bonds formed in alpha1beta1E270Cgamma2 but not in alpha1N275Cbeta1gamma2 or alpha1beta1gamma2K285C. Diazepam potentiation and Zn2+ inhibition demonstrated that expressed receptors contained a gamma subunit. Therefore, the disulfide bond in alpha1beta1E270Cgamma2 formed between non-adjacent subunits. In the homologous acetylcholine receptor 4-A resolution structure, the distance between alpha carbon atoms of 20' aligned positions in non-adjacent subunits is approximately 19 A. Because disulfide trapping involves covalent bond formation, it indicates the extent of movement but does not provide an indication of the energetics of protein deformation. Pairs of cysteines can form high affinity Zn(2+)-binding sites whose affinity depends on the energetics of forming a bidentate-binding site. The Zn2+ inhibition IC50 for alpha1beta1E270Cgamma2 was 34 nm. In contrast, it was greater than 100 microM in alpha1N275Cbeta1gamma2 and alpha1beta1gamma2K285C receptors. The high Zn2+ affinity in alpha1beta1E270Cgamma2 implies that this region in the beta subunit has a high protein mobility with a low energy barrier to translational motions that bring the positions into close proximity. The differential mobility of the extracellular ends of the beta and alpha M2 segments may have important implications for GABA-induced conformational changes during channel gating.

Animals↗
PubMed2004

Role of gamma-aminobutyric acid in early neuronal development: studies with an embryonic neuroectodermal stem cell clone.

gamma-Aminobutyric acid (GABA) has been known to function as an autocrine/paracrine signal molecule in addition to its well-known inhibitory neurotransmitter function. Studies on the developing brain and on primary brain cell cultures provided evidence for a variety of GABA functions in periods preceding the formation of synapses. The exact role of GABA in the early neural development, however, is still not well understood. In this study, one-cell-derived NE-4C neuroectodermal stem cells were induced to form neurons and astrocytes in vitro, and the role of GABA was investigated in defined phases of neurogenesis. Noninduced NE-4C cells contained GABA, expressed GABA(A)R alpha subunits, and carried functional GABA(A) ion channels. A moderate cytoplasmic GABA content was detected during the entire period of differentiation. By the time of the formation of differentiated neurons, neuron-like cells with both high and low GABA content were clearly distinguishable. HPLC analysis indicated that NE-4C cells released GABA into their fluid environment during all stages of neuronal development. By using the patch-clamp technique, GABA-evoked currents were recorded during the entire proliferation/differentiation period, whereas a GABA-evoked increase in intracellular Ca(2+) was detected only during the maturation of postmitotic neuronal precursors. Bicuculline blocked both the ion currents and the [Ca(2+)](i) increase in response to GABA. Neuron formation was facilitated by GABA through GABA(A) ion channels during postmitotic differentiation, but not earlier during the phases of cell fate commitment. Although the data clearly demonstrate an early responsiveness to GABA, understanding the significance of GABA influence in early neural cell fate decisions will require further investigation.

Animals↗
PubMed1991

Organization of neurons labeled by antibodies to gamma-aminobutyric acid (GABA) in the superior colliculus of the Rhesus monkey.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is found in the superior colliculus (SC) of many mammalian species. In cat, several distinct classes of putative GABAergic neuron have been identified using antibodies directed against the neurotransmitter. It is not known whether these classes are found in other species. To study this, we examined the distribution, morphology, ultrastructure, and synaptic organization of GABA immunoreactive neurons in the SC of the Rhesus monkey (Macaca mulatta). Antibody-labeled neurons were distributed throughout the monkey SC, but were most densely concentrated within the zonal and superficial gray layers (32.5% of the total). These neurons were all small cells ranging from 6.6-16.3 microns in average diameter, and had granule, pyriform, and horizontal morphologies. Four types of labeled profile were identified in single ultrathin sections with the electron microscope. Presynaptic dendrites (PSDs) contained pleomorphic vesicles, received synaptic input from unlabeled axon terminals, and sometimes formed symmetric synaptic contacts with postsynaptic profiles. Two subtypes were found. One type contained loose accumulations of synaptic vesicles throughout the profile and had a distinctive varicose shape. The other type contained small discrete clusters of synaptic vesicles near the site of synaptic apposition. The former were much more common. Profiles with typical axon terminal morphology were also found. These profiles usually contained numerous flattened vesicles and formed symmetric synapses with postsynaptic profiles, both dendrites and cell bodies. Some conventional dendrites and myelinated axons were also labeled. Serial ultrathin section reconstructions revealed that PSDs formed complex synaptic relationships with other elements. Retinal terminals, identified by their characteristic pale mitochondria, established synaptic contacts with both types of PSD. These PSDs also established contact with each other, providing a possible anatomical substrate for disinhibition. We conclude that the monkey SC has multiple GABAergic cell types, similar to those found in cat, and may represent an organization common to both mammals and some other vertebrate species. The circuitry established by these cell types may provide a mechanism for disinhibition as well as inhibition in the mammalian SC.

Animals↗
PubMed2000

Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), a selective modulator of gamma-aminobutyric acid(A) receptors.

The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), on gamma-aminobutyric acid(A) receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [(35)S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC(50) value of 230 nM and in human gamma-aminobutyric acid(A) receptor subunit combinations of alpha1beta2gamma2L, alpha2beta2gamma2L, alpha3beta2gamma2L, alpha4beta3gamma2L, alpha5beta2gamma2L, and alpha6beta3gamma2L receptors (IC(50) values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug.

Alprazolam↗
PubMed1992

On the activity of gamma-aminobutyric acid and glutamate transporters in chick embryonic neurons and rat synaptosomes.

The uptake of radioactive gamma-aminobutyric acid (GABA) and D-aspartate and the effect of SKF 89976-A, a non-substrate inhibitor of the GABA transporter, on this uptake have been investigated. Neuronal cultures from eight-day-old chick embryos grown for three or six days in vitro, were used as a model. For comparison, we also used the P2-fraction from rat. Neuronal cultures grown for three and six days expressed high-affinity uptake systems for [3H]GABA and for D-[3H]aspartate with an increasing Vmax during this period. The lipophilic non-substrate GABA uptake inhibitor, SKF 89976-A, inhibited transporter mediated uptake of GABA both in cell cultures from chicken, and in P2-fractions from rat. The results also showed that SKF 89976-A was a poor inhibitor of the uptake of D-aspartate. We found no non-saturable uptake of D-aspartate.

Amino Acid Transport System X-AG↗
PubMed1987

In vivo effects of gamma-aminobutyric acid on the urinary bladder contraction accompanying micturition.

We studied the effects of the gamma-aminobutyric acid (GABA) receptor agonists, diazepam and muscimol, on the urinary bladder contraction induced by infusion of Tyrode's solution into the bladder in anesthetized rats. Diazepam (1 mg/kg, i.p.) completely inhibited bladder contraction, causing the bladder pressure to rise until solution leaked from the penis. The inhibitory effects of diazepam were reversed by picrotoxin (1 mg/kg, i.v., twice with an interval of 10 min), and the effects were potentiated and attenuated by pretreatment with aminooxyacetic acid (AA, 10 mg/kg, i.v.) and semicarbazide (200 mg/kg, i.v.), respectively. Only pretreatment with AA inhibited the bladder contraction induced by infusion of Tyrode's solution into the bladder in six out of eight rats. Diazepam abolished efferent discharges recorded from the left pelvic nerve, but hexamethonium facilitated the generation of efferent discharges after inhibition of bladder contraction. After complete inhibition of bladder contraction by diazepam, electrical stimulation of the left pelvic nerve at 5 Hz for 30 sec was able to induce bladder contraction, and this resulted in micturition. Intracerebroventricular injection or intrathecal injection into the sacral part of the spinal cord of 1 microgram muscimol completely inhibited the bladder contraction. It was considered that the inhibitory effects of GABA receptor agonists on bladder contraction were mainly induced through the GABA receptors in the micturition center of the sacral cord, as well as the brain stem.

Aminooxyacetic Acid↗
PubMed1999

The alpha9 nicotinic acetylcholine receptor shares pharmacological properties with type A gamma-aminobutyric acid, glycine, and type 3 serotonin receptors.

In the present study, we provide evidence that the alpha9 nicotinic acetylcholine receptor (nAChR) shares pharmacological properties with members of the Cys-loop family of receptors. Thus, the type A gamma-aminobutyric acid receptor antagonist bicuculline, the glycinergic antagonist strychnine, and the type 3 serotonin receptor antagonist ICS-205,930 block ACh-evoked currents in alpha9-injected Xenopus laevis oocytes with the following rank order of potency: strychnine > ICS-205,930 > bicuculline. Block by antagonists was reflected in an increase in the acetylcholine (ACh) EC50 value, with no changes in agonist maximal response or Hill coefficient, which suggests a competitive type of block. Moreover, whereas neither gamma-aminobutyric acid nor glycine modified ACh-evoked currents, serotonin blocked responses to ACh in a concentration-dependent manner. The present results suggest that the alpha9 nAChR must conserve in its primary structure some residues responsible for ligand binding common to other Cys-loop receptors. In addition, it adds further evidence that the alpha9 nAChR and the cholinergic receptor present at the base of cochlear outer hair cells have similar pharmacological properties.

Acetylcholine↗
PubMed2006

Collision-induced dissociation of protonated tetrapeptides containing beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid or 4-aminomethylbenzoic acid residues.

The influence of the presence and position of a single beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid or 4-aminomethylbenzoic acid residue on the tendency to form b(n)+ -and y(n)+ -type product ions was determined using a group of protonated tetrapeptides with general sequence XAAG, AXAG and AAXG (where X refers to the position of amino acid substitution). The hypothesis tested was that the 'alternative' amino acids would influence product ion signal intensities by inhibiting or suppressing either the nucleophilic attack or key proton transfer steps by forcing the adoption of large cyclic intermediates or blocking cyclization altogether. We found that specific b ions are diminished or eliminated completely when betaA, gammaAbu, Cap or 4AMBz residues are positioned such that they should interfere with the intramolecular nucleophilic attack step. In addition, differences in the relative proton affinities of the alternative amino acids influence the competition between complementary b(n) and y(n) ions. For both the AXAG and the XAAG series of peptides, collision-induced dissociation (CID) generated prominent b ions despite potential inhibition or suppression of intramolecular proton migration by the betaA, gammaAbu, Cap or 4AMBz residues. The prominent appearance of b ions from the AXAG and XAAG peptide is noteworthy, and suggests either that proton migration occurs through larger, 'whole' peptide cyclic intermediates or that fragmentation proceeds through a population of [M+H]+ isomers that are initially protonated at amide O atoms.

4-Aminobenzoic Acid↗
PubMed1990

[The cross desensitization and modulation of Cl currents activated by gamma-aminobutyric acid and L-glutamate in the isolated neurons of Aplysia].

Chlorine conductance gated by gamma-aminobutyric acid (GABA) and L-glutamate in the medial pleural neurons of aplysia was studied using voltage clamp technique and a continuous microperfusion system that allowed rapid agonist application. Both GABA and glutamate elicited current responses that rapidly activated and then decayed. Glutamate response could be blocked by perfusion of aspartate or taurine and the GABA current showed voltage dependence. Thus the currents exhibited cross desensitization. It has been found that very low concentrations of acetylcholine (10(-8) to 10(-14) M) which have no electrophysiologic responses of their own, modulate the response to a constant application of GABA. During cooling the preparation blocked this effect, it is possible to suggest that the small doses of acetylcholine effect the membrane chemosensitivity through the cell biochemical mechanism.

Animals↗
PubMed1985

Possible inhibitory role of endogenous gamma-aminobutyric acid in the nonnicotinic functions of the dog cardiac sympathetic ganglia.

Participation of endogenous gamma-aminobutyric acid (GABA) in the functions of dog cardiac ganglia was investigated. The ganglionic stimulants as well as agents affecting GABA system were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.), unless otherwise mentioned. Inhibition of endogenous GABA degradation by the GABA-transaminase inhibitor, aminooxyacetic acid (AOAA) administered 10 mg/kg i.v. 2 hr before completion of surgical procedures did not alter the positive chronotropic responses to bethanecol (25 and 50 micrograms) and acetylcholine (25, 50 and 100 micrograms) but reduced markedly those to angiotensin II (1 and 2 micrograms). This reduction was antagonized by picrotoxin (5 mg). Diazepam given 10 mg/kg i.v. also inhibited the ganglionic responses to angiotensin II in both untreated and AOAA-pretreated dogs, this inhibition by diazepam being more marked in the AOAA-pretreated than in the untreated dogs. The same dose of diazepam did not affect the responses to acetylcholine but reduced to a certain degree of responses to bethanechol in the AOAA-pretreated dogs. These inhibitions by diazepam were also reversed by picrotoxin. After i.v. treatment with the glutamic acid decarboxylase inhibitors, 3-mercaptopropionic acid (50 mg/kg) or isoniazid (200 mg/kg), the ganglionic responses to angiotensin II were not altered, but inhibitory effects of diazepam on the responses to angiotensin II were eliminated after 3-mercaptopropionic acid but not after isoniazid. These results suggest that endogenous GABA may play an inhibitory role in the nonnicotinic ganglionic pathways and that diazepam probably exerts a ganglionic action through endogenous GABAergic mechanisms.

3-Mercaptopropionic Acid↗